WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy

Daniela Bakula; Amelie J Müller; Theresia Zuleger; Zsuzsanna Takacs; Mirita Franz-Wachtel; Ann-Katrin Thost; Daniel Brigger; Mario P Tschan; Tancred Frickey; Horst Robenek; Boris Macek; Tassula Proikas-Cezanne

doi:10.1038/ncomms15637

WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy

Nat Commun. 2017 May 31:8:15637. doi: 10.1038/ncomms15637.

Authors

Daniela Bakula^{1

2}, Amelie J Müller^{1

2}, Theresia Zuleger¹, Zsuzsanna Takacs^{1

2}, Mirita Franz-Wachtel³, Ann-Katrin Thost¹, Daniel Brigger⁴, Mario P Tschan⁴, Tancred Frickey⁵, Horst Robenek⁶, Boris Macek^{2

3}, Tassula Proikas-Cezanne^{1

2}

Affiliations

¹ Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
² International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
³ Proteome Center Tuebingen, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
⁴ Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
⁵ Department of Biology, Applied Bioinformatics, Konstanz University, D-78457 Konstanz, Germany.
⁶ Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, D-48149 Muenster, Germany.

Abstract

Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes. Upstream, WIPI3 associates with AMPK-activated TSC complex at lysosomes, regulating mTOR. Our WIPI interactome analysis reveals the scaffold functions of WIPI proteins interconnecting autophagy signal control and autophagosome formation. Our functional kinase screen uncovers a novel regulatory link between LKB1-mediated AMPK stimulation that produces a direct signal via WIPI4, and we show that the AMPK-related kinases NUAK2 and BRSK2 regulate autophagy through WIPI4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases / chemistry
Adaptor Proteins, Signal Transducing / metabolism
Autophagy*
Autophagy-Related Protein-1 Homolog / chemistry
Autophagy-Related Proteins / chemistry
Carrier Proteins / chemistry*
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
Intracellular Signaling Peptides and Proteins / chemistry
Lysosomes / metabolism
Phagosomes / metabolism
Phosphatidylinositol Phosphates / chemistry
Protein Binding
Protein Conformation
Protein Serine-Threonine Kinases / chemistry*
Signal Transduction*
Vesicular Transport Proteins / chemistry

Substances

ATG2B protein, human
Adaptor Proteins, Signal Transducing
Autophagy-Related Proteins
Carrier Proteins
Intracellular Signaling Peptides and Proteins
Phosphatidylinositol Phosphates
Vesicular Transport Proteins
WDR45 protein, human
WDR45B protein, human
phosphatidylinositol 3-phosphate
Autophagy-Related Protein-1 Homolog
Protein Serine-Threonine Kinases
STK11 protein, human
ULK1 protein, human
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases
PRKAA1 protein, human